Pressurized metered dose inhalers and method of manufacture

Abstract

The disclosure relates to a pressurized Metered Dose Inhaler-compatible tablet, i.e. one that is able to be dispersed or disintegrates within a liquid phase propellant, which is used in a pressurized Metered Dose Inhaler formulation containing at least one active pharmaceutical ingredient and one or more excipients.

Claims

1. A tablet for use in a pressurized metered dose inhaler (pMDI) comprising: i) at least one micronized active pharmaceutical ingredient (API); ii) at least one excipient provided as a particulate carrier material having a size range between 15 μm-200 μm; and iii) menthol provided as a disintegrant at a concentration of about 1% w/w relative to said at least one excipient; wherein menthol is mixed with, or coated onto, said at least one excipient and compressed with said micronized API to form said tablet, whereby upon exposure to the liquid phase propellant the menthol dissolves and the tablet breaks down leaving a suspension and/or solution of said API and a suspension of the excipient in said propellant.

2. The tablet according to claim 1 wherein the at least one micronized API is a respiratory therapeutic.

3. The tablet according to claim 2 wherein the at least one micronized API is for treating one or more of the following diseases or conditions: asthma, bronchitis, COPD, chest infections, acute pain relief, migraine, disorders of hormonal imbalance and cardiovascular disease.

4. The tablet according to claim 1 wherein said propellant is a hydrofluorocarbon selected from the group consisting of a hydrofluoroalkane (HFA), a hydrofluoroolefin and mixtures thereof.

5. The tablet according to claim 1 wherein the at least one excipient is selected from the group consisting of a monosaccharide, disaccharide, trisaccharide, oligosaccharide, polysaccharide, any physiologically acceptable derivative thereof, salt thereof, solvate thereof, and any mixture thereof.

6. The tablet according to claim 1 wherein the at least one excipient is coated with menthol.

7. The tablet according to claim 1 wherein the at least one excipient is lactose or leucine.

8. The tablet according to claim 7 wherein the at least one excipient is lactose.

9. The tablet according to claim 1 wherein the at least one API is soluble in the liquid phase.

10. The tablet according to claim 1 wherein the at least one API is insoluble in the liquid phase.

11. The tablet according to claim 1 wherein said tablet comprises a plurality of APIs.

12. The tablet according to claim 1 wherein said tablet comprises one or more API(s) soluble in the liquid phase and one or more API(s) insoluble in the liquid phase.

13. The tablet according to claim 1 wherein said menthol is coated onto said one or more APIs.

14. The tablet according to claim 4 wherein said propellant is a HFA selected from the group consisting of HFA 134a, HFA 227a, and a mixture thereof.

15. The tablet according to claim 1, wherein the at least one excipient is selected from the group consisting of a dipeptide, a tripeptide, an oligopeptide, a polypeptide, a protein, a physiologically acceptable derivative thereof, a physiologically acceptable salt thereof, a physiologically acceptable solvate thereof, and a mixture thereof.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The Invention will now be described by way of example only with reference to the Examples below and to the following Figures wherein:

(2) FIG. 1. Distribution Pattern of Recovered Salbutamol Sulphate (SS) (%) from the NGI for Test, Control and Reference Formulations.

(3) Table 1. Solubility Estimates of Glycerol, Tween 80 and PEG 400 in HFA 134a.

(4) Table 2. Solubility Estimates (Low Concentration) of Menthol, PVP, PEG 6000, PG, Sodium Bicarbonate and Citric Acid in Propellants 227 (*) and 134a (#).

(5) Table 3. Solubility Estimates (High Concentration) of Menthol, PVP, and PG in Propellant 227 (*) and 134a (#).

(6) Table 4. Theoretical Concentrations (% w/w) of Additive Coated onto Lactose Samples.

(7) Table 5. Theoretical Concentrations (% w/w) of Salbutamol Sulphate Combined with Coated Lactose Samples (excipient and disintegrant) and Uncoated Lactose Control.

(8) Table 6. Content Uniformity Data for Coated (excipient and disintegrant) and Uncoated (excipient-Control) SS:Lactose Samples.

(9) Table 7. pMDI Formulations Used for Aerosol Testing. Test formulation=Lactose coated with 1% w/w Menthol Compressed into Tablet (excipient and disintegrant) (*). Control Formulation=Lactose Coated with 1% w/w Menthol Uncompressed (excipient and disintegrant) (#). Control Formulation=Uncoated Lactose Uncompressed (§) (excipient only).

(10) Table 8. Summary of Aerosol Characteristics Using 0.35 mm Actuator Orifice Diameter. Test Formulation=Lactose Coated with 1% w/w Menthol Compressed into Tablet (excipient and disintegrant) (*). Control Formulation=Lactose Coated with 1% w/w Menthol Uncompressed (excipient and disintegrant) (#). Control Formulation=Uncoated Lactose Uncompressed (excipient only)—(§). FPF refers to the fine particle fraction, i.e. the % recovered API with a particle size less than 5 μm. FPD refers to the fine particle mass i.e. the mass of recovered API with a particle size less than 5 μm. MMAD refers to the mass median aerodynamic diameter, and GSD refers to the geometric standard deviation of the particle size distribution.

(11) Table 9. Summary of Percentage Recovery of SS from the NGI for Test Formulation (*; Lactose Coated with 1% w/w Menthol Compressed into Tablet—excipient and disintegrant), 1% Menthol Control (#; lactose coated with 1% w/w Menthol uncompressed—excipient and disintegrant), Lactose Control (§; uncoated lactose (excipient) Uncompressed i.e. no disintegrant) and Reference Formulations (Commercial Ventolin® Evohaler Product). ECD refers to effective cut-off diameter (μm). MOC refers to Micro orifice collector.

(12) Table 10. Theoretical Concentrations (% w/w) of Salmeterol Xinafoate and Fluticasone Propionate Combined with Coated Lactose Samples.

(13) Table 11. Content Uniformity Data for Coated and Un-coated 1:8.6(SX)/2.5(FP):Lactose Samples.

(14) Table 12. Content Uniformity Data for Coated and Un-coated 1:17.2(SX)/5(FP):Lactose Samples.

(15) Table 13. Salmeterol xinafoate (SX):Fluticasone Propionate (FP) Combination Formulations Containing Lactose used for Aerosol Testing. The ratios (weight:weight) for API:lactose were 1:8.6 for SX and 1:2.5 for FP (*Control Formulation=Uncoated Lactose compressed into tablet; #Test Formulation=Lactose coated with 1% w/w Menthol compressed into tablet; ¥Control Formulation=Lactose coated with 1% w/w Menthol uncompressed).

(16) Table 14. Salmeterol xinafoate (SX):Fluticasone Propionate (FP) Combination Formulations Containing Lactose Used for Aerosol Testing. The ratios (weight:weight) for API:lactose were 1:17.2 for SX and 1:5 for FP (*Control Formulation=Uncoated Lactose compressed into tablet; #Test Formulation=Lactose coated with 1% w/w Menthol Compressed into Tablet; ¥Control Formulation=Lactose coated with 1% w/w Menthol Uncompressed).

(17) Table 15. Summary of Aerosol Characteristics of Salmeterol xinafoate from a Salmeterol xinafoate (SX):Fluticasone Propionate (FP) Combination Formulation Containing Lactose. The ratios (weight:weight) for API:lactose were 1:8.6 for SX and 1:2.5 for FP. Testing was performed using a 0.25 mm Actuator Orifice Diameter (Mean values n=3, ±SD).

(18) Table 16. Summary of Aerosol Characteristics of Fluticasone Propionate from a Salmeterol xinafoate (SX):Fluticasone Propionate (FP) Combination Formulation Containing Lactose. The ratios (weight:weight) for API:lactose were 1:8.6 for SX and 1:2.5 for FP. Testing was performed using a 0.25 mm Actuator Orifice Diameter (Mean values n=3, ±SD).

(19) Table 17. Summary of Aerosol Characteristics of Salmeterol xinafoate from a Salmeterol Xinafoate (SX):Fluticasone Propionate (FP) Combination Formulation Containing Lactose. The ratios (weight:weight) for API:lactose were 1:17.2 for SX and 1:5 for FP. Testing was performed using a 0.25 mm Actuator Orifice Diameter (Mean values n=3, ±SD).

(20) Table 18. Summary of Aerosol Characteristics of Fluticasone Propionate from a Salmeterol xinafoate (SX):Fluticasone Propionate (FP) Combination Formulation Containing Lactose. The ratios (weight:weight) for API:lactose were 1:17.2 for SX and 1:5 for FP. Testing was performed using a 0.25 mm Actuator Orifice Diameter (Mean values n=3, ±SD).

(21) Table 19. Summary of Content Uniformity Illustrating Recovery (%) of BDP from BDP:Lactose Powder Blends (1:2 and 1:5 weight in weight blends of BDP and Lactose)

(22) Table 20. Summary of Dose Characteristics of BDP Solution Formulations (0.4 mm actuator orifice diameter). Test tablets were prepared from 1:5 BDP:Lactose blends (w/w) with lactose coated with 1% w/w menthol. Control tablets consisted of BDP with uncoated lactose. Additional controls included uncompressed powder formulations and BDP powder alone added directly to the HFA 134a:ethanol propellant system.

(23) Table 21. Summary of Dose Characteristics of BDP Solution Formulations (0.25 mm actuator orifice diameter). These are the same test canisters as those described in Tables 24 and 25.

(24) Table 22. Summary of Content Uniformity Illustrating Recovery (%) of BDP & SS from Lactose Powder Blends. The weight:weight (w/w) ratios for API:lactose were 1:12 for BDP and 1:5 for Salbutamol Sulphate.

(25) Table 23. Summary of Dose Characteristics of BDP:SS Combination Formulations (0.25 mm actuator orifice diameter)—BDP Performance. The weight:weight (w/w) ratios for API:lactose were 1:12 for BDP and 1:5 for Salbutamol Sulphate. Test tablets were prepared from lactose coated with 1% w/w menthol. Control tablets consisted of blends of the APIs with uncoated lactose.

(26) Table 24. Summary of Dose Characteristics of BDP:SS Combination Formulations (0.25 mm actuator orifice diameter)—SS Performance. The weight:weight (w/w) ratios for API:lactose were 1:12 for BDP and 1:5 for Salbutamol Sulphate. Test tablets were prepared from lactose coated with 1% w/w menthol. Control tablets consisted of blends of the APIs with uncoated lactose.

DETAILED DESCRIPTION

(27) Materials and Methods

(28) Solubility of Potential Disintegrants

(29) The solubility of some potential disintegrants was estimated by weighing samples directly into plastic coated glass aerosol bottles or clear polyethylene terephthalate (PET) aerosol vials, sealing with metering valves and filling a known amount of propellant (HFA 134a or HFA 227ea,) directly into the vials using laboratory scale pressure filling equipment. Samples of glycerol, Tween 80 and PEG (polyethylene glycol) 400 were investigated in propellant HFA 134a. Menthol, PVP (polyvinylpolypyrrolidone) (molecular weight 36,000), PEG 6000, PG (propylene glycol), and also citric acid and sodium bicarbonate which have potential disintegrant properties were investigated in both propellants i.e. HFA 134a and 227.

(30) Coating Lactose Bulk Samples

(31) Separate samples of lactose were coated with either 1% or 5% w/w glycerol, PEG 400 or Tween 80 or with 1% w/w Menthol, PVP (molecular weight 360,000), PEG 6000, or propylene glycol (PG,).

(32) For the 1% w/w samples of disintegrant approximately 0.2 g of disintegrant was added to 19.8 g of lactose. For the 5% w/w samples of disintegrant approximately 1 g of disintegrant was added to 19 g of lactose.

(33) The disintegrants were dissolved in absolute ethanol and coated onto the lactose as follows. The disintegrant was added to a glass screw cap jar (50 mL) and a small amount of ethanol sufficient to dissolve the disintegrant was added. Subsequently the lactose was slowly introduced in discrete amounts followed by vigorous shaking of the jar upon each addition of lactose. The process was repeated until all the lactose was added to the jar and, if necessary (to ensure good wetting and dispersion of the lactose), further ethanol was added. Care was taken to ensure that the minimal amount of ethanol was used (enough to allow effective shaking of the contents and therefore coating of the lactose with disintegrant). Following shaking the contents were transferred to a 2 L Pyrex beaker and dried on stirrer/hotplate and the powdered coated lactose was recovered and stored in plastic zip-lok bags.

(34) Preliminary Tablet Formulation I—No API

(35) Initial tablet testing was performed using lactose coated with either 1 or 5% w/w PEG 400, and either 1% w/w glycerol or Tween 80. Samples of lactose coated with these potential disintegrants were compressed into tablets using a bench top tabletting machine fitted with a caplet punch and die assembly. Tablets were individually manufactured with the compression force setting no greater than 60 KN. Samples of lactose alone were used as controls. Typical tablet weights were approximately 0.4 g.

(36) Test Formulation 1—Salbutamol Sulphate (SS):Coated Lactose

(37) Proof of concept was proved using SS as a model API to blend with the coated lactose. Micronised SS was blended with coated lactose so that the final product contained approximately 5% w/w SS. Batch sizes were approximately 9.45 g total powder. Samples of the treated lactose were blended with the SS by passing through a 90 μm test sieve and transferred to a glass mortar. Thereafter the remaining coated lactose was added to the mortar so as to ensure geometric dilution of the mortar contents, which were mixed with a spatula. The powder blend was transferred to a stainless steel screw cap jar, secured in a low shear mixer and tumbled for 10 min at 46 rpm.

(38) Batches were prepared in this way with lactose coated with 1% w/w menthol, PVP and PG.

(39) Test Formulation 2—Combination of Insoluble APIs Salmeterol Xinafoate and Fluticasone propionate

(40) Salmeterol Xinafoate and Fluticasone propionate were selected as a model API combination to blend with the lactose (coated or uncoated). Lactose was blended with the APIs so that the final product contained 7.8% and 26.9% w/w SX and FP respectively in a 1:8.6 (SX)/1:2.5 (FP):Lactose formulation and 4.7% and 16.3% w/w SX and FP respectively in a 1:17.2 (SX)/5 (FP):Lactose formulation. The target dose was 36.3 μg of SX (25 μg salmeterol) and 125 μg of FP per actuation from the valve and 30.5 μg (21 μg salmeterol) SX and 110 μg of FP from the actuator, the metering valve volume was 50 μL.

(41) Batch sizes were approximately 4.48 and 4.94 g total powder for 1:8.6 (SX)/1:2.5 (FP) and 1:17.2 (SX)/1:5 (FP):Lactose formulations respectively. Samples of the coated lactose were blended with the SX:FP by adding discrete amounts of lactose to a glass mortar, and mixing with a spatula at each addition, to ensure geometric dilution of the APIs. The powder blend was transferred to a stainless steel screw cap jar, secured in a low shear mixer and tumbled for 10 min at 46 rpm.

(42) 1:8.6 (SX)/1:2.5 (FP) % w/w:Lactose tablets were manufactured using menthol coated lactose using a bench top tabletting machine fitted with a punch (upper and lower punch diameter 6 mm) and die (6.0 mm) assembly. Tablets were individually manufactured with uncoated and 1% coated lactose.

(43) 1:17.2 (SX)/1:5 (FP) % w/w:Lactose Tablets were individually manufactured with uncoated and 1% coated lactose.

(44) Test Formulation 3—1:5 w/w BDP:Lactose (control, un-coated lactose)

(45) Beclometasone Dipropionate (non-micronised) was selected as a model API to blend with the lactose both coated or uncoated. Lactose was blended with API so that the final product contained approximately 16.7% w/w BDP (approx 1:5 Lactose:BDP). The target dose was 50 μg of BDP per actuation, the metering valve volume was 50 μL.

(46) Batch sizes were approximately 4.35 g total powder. Samples of the uncoated lactose were blended with the BDP by adding discrete amounts of lactose and BDP to a glass mortar, and mixing with a spatula at each addition, to ensure geometric dilution of the API. The powder blend was transferred to a stainless steel screw cap jar, secured in a low shear mixer and tumbled for 10 min at 46 rpm.

(47) 1:5 w/w BDP:Lactose compressed dosage forms were manufactured using uncoated lactose or 1% w/w menthol coated lactose using a bench top tabletting machine fitted with a punch and die assembly designed to produce 0.6 mm diameter round, flat face, bevelled edged tablets. Tablets were individually manufactured.

(48) 1:2 w/w BDP:Lactose was blended with the uncoated lactose so that the final product contained approximately 33.3% w/w BDP. Batch sizes were approximately 2.18 g total powder. Samples of the uncoated lactose were blended with the BDP in the same manner described for the 1:5 formulations. Coated formulations were repeated with the same bulk lactose coated with 1% w/w menthol.

(49) Test Formulation 4—1:12 BDP:Lactose and approx. 1:5 SS:Lactose)

(50) BDP and micronised salbutamol sulphate were blended with uncoated lactose so that the final product contained approximately 5%, and 12% w/w BDP and SS respectively. Batch sizes were approximately 5.56 g total powder. Samples of the uncoated lactose were blended with the SS and BDP by passing through a 90 μm test sieve and transferred to a glass mortar and thoroughly mixed. Thereafter, the remaining uncoated lactose was added to the mortar so as to ensure geometric dilution of the mortar contents, which were mixed with a spatula. The powder blend was transferred to a stainless steel screw cap jar, secured in a low shear mixer and tumbled for 10 min at 46 rpm.

(51) Content Uniformity

(52) The content uniformity of the powder blends was determined as follows: three samples were randomly taken from the bulk powder blends and accurately weighed into 100 mL flasks and diluted to volume with HPLC grade water. Following mixing, 50 μL samples were withdrawn and transferred to 10 mL volumetric flasks and diluted to volume. SS was quantified using a validated high performance liquid chromatography (HPLC) method. SX:FP, BDP, BDP/SS were quantified using a validated high performance liquid chromatography (HPLC) method.

(53) Preliminary Disintegration Tests

(54) Samples of the tablets were individually weighed and dispensed into glass aerosol vials and 50 μL metering valves were crimped to seal the containers. HFA 134a was added in appropriate amounts via the valve and the weight of propellant dispensed into the can was recorded. In some cases the preparations were sonicated using a sonic bath or placed on a mechanical flask shaker. To facilitate more readily dispersed formulations, a ball bearing or plastic pea may be dispensed into the can during manufacture.

(55) Preliminary Aerosol Testing—Particle Size Distribution

(56) Samples of the tablets prepared using 1% menthol coated lactose and blended with SS were used for aerosol testing. The tablets were dispensed into glass aerosol vials or PET vials, and 19 mL fluorocarbon polymerised aluminium canisters. 50 μL metering valves were crimped to seal the vials and propellant HFA 134a was filled.

(57) In the case of soluble API formulations, the vial containing the tablet was placed into a mixture of dry ice/acetone in a Dewar flask along with pre-prepared canister of 5% (w/w) ethanol in HFA 134a propellant. Both the vial containing tablet and the canister containing the 5% ethanol in propellant HFA 134a were cooled in the dry ice/acetone mixture for at least 5 min. The canister of ethanol and propellant was securely clamped and the valve was removed, the contents were carefully poured into the pre-cooled can containing the tablet and the valve was placed on the can and without delay the valve was crimped securely in place.

(58) In addition to the tablet preparations, powder blends (uncompressed controls) were investigated. For example, a sample of SS:coated lactose blend that had not been compressed into a construct, and the second was an equivalent ratio of SS:lactose in which the lactose had neither been coated nor compressed into a tablet.

(59) The formulations and the control preparations were tested using actuators with 0.35 mm orifice diameters unless otherwise stated.

(60) The aerodynamic particle size distribution of the emitted aerosols was determined by inertial impaction testing using a Next Generation Impactor (NGI) operated at a standard flow rate of 30 L/min. Recovered API samples were quantified by validated HPLC assay. One of the key aerosol characteristics determined from the NGI tests was the fine particle fraction (FPF), i.e. the % of the recovered API with an aerodynamic particle size less than 5 μm. It is generally regarded that particles with aerodynamic diameters of less than 5 μm will penetrate into the lower airways. Other key parameters evaluated from the NGI particle size distribution data were the fine particle dose (FPD) i.e. the amount (μg) of API with an aerodynamic particle size less than 5 μm.

(61) Results

(62) In order to investigate the feasibility of the proposed formulation approach a series of preliminary experiments were conducted to assess some of the key variables.

(63) The strategy was to establish the solubility of proposed disintegrants in propellants HFA 134a and 227. Thereafter samples of lactose were coated with the most suitable disintegrant materials and compressed into tablets using a bench top tableting machine.

(64) Following these experiments candidate disintegrants were coated onto lactose and blended with a model API i.e. salbutamol sulphate (SS). The powder blends were characterised in terms of content uniformity i.e. established that each unit dose of powder contained the calculated dose of SS.

(65) Samples of the SS:coated lactose blends were compressed into tablets and dispensed into canisters and filled with propellant. Control samples consisted of the same powder blend dispensed into canisters without compaction into tablets, and also an equivalent SS:lactose blend with non-coated non-compressed lactose. The aerosol properties of these formulations were assessed and compared to a reference product i.e. Ventolin® (Evohaler, GSK, UK).

(66) Solubility Results

(67) Table 1 shows the observations relating to visual estimates of the solubility of glycerol, Tween 80 and PEG 400 in HFA 134a. It was determined that glycerol at a concentration of 0.063% w/w was not soluble in HFA 134a alone. The other materials at the low concentrations investigated were soluble.

(68) Table 2 shows the observations relating to the solubility of other potential disintegrants in propellants 134a and 227. Menthol and PG appeared soluble in both propellants at the concentrations investigated. PVP was observed to be soluble in HFA 227 but not in HFA 134a. PEG 6000, sodium bicarbonate and citric acid were insoluble in both propellants at the concentrations investigated but are likely to be soluble in ethanol blends of the propellant.

(69) Further solubility tests were performed for Menthol, PVP and PG to determine solubility at higher concentrations. The results are shown in Table 3.

(70) Lactose Coating

(71) Based on the actual weights of lactose and disintegrant materials used in the coating process, the concentrations on a % w/w basis for the six materials (i.e. Glycerol, PEG 400, Tween 80, Menthol, PVP and PG) observed to have some solubility in HFA propellants are shown in Table 4.

EXAMPLE 1

(72) 1.1 Preliminary Tablet Formulation 1—No API

(73) Based on the solubility observations in Table 1, preliminary tablet formulations were prepared using lactose coated with 5% w/w PEG 400, 1% w/w PEG 400, 1% w/w Tween 80 or 1% w/w glycerol. Uncoated lactose was used a as control.

(74) The 5% PEG 400 formulations had a greater tendency to disintegrate in HFA 134a than the 1% PEG 400, which was more effectively dispersed than 1% Tween 80, which in turn was more effectively dispersed than 1% glycerol. Order of disintegration was therefore 5% PEG 400>1% PEG 400>1% Tween>1% glycerol. It was found that although vigorous hand shaking caused a small amount of dispersion that sonication (or ball bearing/plastic ‘pea’ agitation) was necessary to fully disperse the 5% PEG 400 tablet.

(75) The lactose only formulation showed no sign of dispersion following prolonged sonication i.e. >15 min. Thus it may be concluded that distintegrants were therefore necessary for dispersal of tablets formulated from lactose alone.

(76) Table 2 showed that menthol, PVP and PG also had some solubility in HFA 134a and/or 227. Table 3 showed that the greatest levels of solubility were observed for menthol. Tablet formulations were subsequently prepared with lactose coated with 1% w/w menthol, PVP, and PG.

(77) The percent of disintegrant as a proportion of the weight of lactose carrier is shown in Table 4.

(78) 1.2 Tablet Formulations with Selected Disintegrants were Readily Dispersible

(79) Samples of tablets containing lactose coated with 1% menthol were observed to be most readily re-dispersed upon addition of HFA 134a. Shaking by hand was sufficient to cause disruption of the dosage form while short sonication (3 min) was found to remove visible aggregates. The 1% PVP and PG formulations were not as readily disrupted although the PG dosage form dispersed to a greater extent that the PVP tablet. The formulations were placed on a mechanical flask shaker for 1 h but large aggregates remained in the PG and PVP formulations. The vials were sonicated for 3 minutes and the number and size of the aggregates was reduced, however more and bigger aggregates remained in the PVP sample compared to the PG sample.

EXAMPLE 2

(80) 2.1 Test Formulation 1: Salbutamol Sulphate (SS):Coated Lactose

(81) The formulations were designed to deliver approximately 100 μg of salbutamol base from the mouthpiece i.e. to enable comparison with a reference product Ventolin® Evohaler (GlaxoSmithKline, UK) i.e. a commercially available form of micronised salbutamol sulphate suspended in HFA 134a. Ventolin was tested using its standard actuator.

(82) The theoretical concentrations of salbutamol sulphate (SS) in the blends manufactured with coated lactose are shown in Table 5. For the control sample, SS was blended with uncoated lactose. All other samples contain the same batch of lactose following coating with the specified additives.

(83) Table 6 shows the content uniformity for powder blends prepared from SS and coated and uncoated (control) lactose samples. The actual measured SS content of the blends as determined by HPLC was compared to the theoretical content determined from the known masses of SS and lactose used for manufacture. The mean values were all within ±7% of the theoretical values.

(84) The variability of the measured concentrations were all less than 3% RSD indicating homogeneous distribution of the SS with the lactose.

(85) The same batches of lactose and SS were used for the manufacture of all blends.

(86) 2.2 Preliminary Aerosol Characterisation

(87) Samples of tablets prepared from SS blended with lactose coated with 1% w/w menthol were dispensed into aerosol containers and HFA 134a was added. For control purposes pMDI were also prepared from a sample of the SS:coated lactose batch that had not been compressed into tablets, and a batch of SS prepared with uncoated lactose that was not compressed into tablets. All batches contained SS at a nominal concentration of 5% w/w relative to the lactose i.e. 1:20 weight:weight (w/w) SS:lactose.

(88) The constituents of the manufactured pMDI are shown in Table 7. Following manufacture the pMDI vials containing the tablet formulations with 1% coated menthol were shaken vigorously by hand which caused initial significant disruption of the tablets. However, on close inspection some small aggregates were still visible in the pMDI vials, consequently the vials were sonicated for 3×3 min which appeared to effectively disrupt the aggregates. No such aggregates were observed for the two control formulations.

(89) Initial testing of the samples indicated that there was a propensity for the valve stem/actuator of the pMDI to block after a small number of actuations.

(90) However, the properties of the emitted aerosol were well suited to inhalation therapy with 42% of the emitted SS recovered in the respirable range i.e. <5 μm aerodynamic diameter (Table 8). In terms of FPF (43%) the performance of the control formulations prepared from coated lactose was very similar to the novel formulation approach.

(91) The mean emitted doses for the novel formulation and the uncoated lactose control were close to the theoretical values. The SS recovery from the coated lactose control was greater than the theoretical value.

(92) The recovery of SS and the deposition pattern of SS in the NGI for the test formulation (compressed SS:menthol coated lactose), the control formulations (uncompressed SS:menthol coated lactose, and SS:uncompressed, uncoated lactose) and the reference product (Ventolin® Evohaler) are shown in Table 9 and the Figure.

(93) Ventolin® Evohaler was tested alongside the novel formulation and control samples. In general there was good agreement between the FPF and FPD for test and reference products. The API recovery from the Induction Port and Stage 1 for the novel formulation was close to that recovered from the Induction Port for the Ventolin® reference product. The fraction of API recovered from Stages 4, 5 and 6 for the novel formulation showed a similar distribution to that of the Reference product.

EXAMPLE 3

(94) 3.1 Test Formulation 2—Salmeterol Xinafoate and Fluticasone propionate

(95) Propellant disintegratable compressed dosage forms (tablets) containing a combination of two propellants (where propellant is specified earlier as being a blend or contain ethanol or other acceptable excipients), insoluble API's namely, fluticasone propionate (FP) and salmeterol xinafoate (SX), were prepared and used to formulate pressurized metered dose inhalers. Such combinations of a bronchodilator and an anti-inflammatory agent are commonly used in the therapy of asthma and COPD.

(96) The formulations were designed to deliver approximately 36.3 μg of SX and 125 μg of FP per metered dose (120 doses) i.e. to be comparable with the Seretide® Evohaler® (Reference product, Glaxo Wellcome UK Limited, UK) a commercially available suspension form of salmeterol xinafoate and fluticasone propionate in HFA 134a. Seretide was tested using its standard actuator.

(97) The theoretical concentrations of SX and FP in the blends manufactured with coated lactose are shown in Table 10. For the control sample SX and FP was blended with uncoated lactose.

(98) Tables 11 and 12 show the content uniformity for powder blends prepared from SX:FP and coated and uncoated lactose samples. The actual measured SX:FP content of the blends as determined by HPLC was compared to the theoretical content determined from the known masses of SX:FP and lactose used for manufacture. The mean values were all within ±4% of the theoretical values.

(99) The variability of the measured concentrations were all less than 3% RSD indicating homogeneous distribution of the SX:FP with the lactose.

(100) The same batches of lactose, SS and FP were used for the manufacture of all blends.

(101) 3.2 Preliminary Tablet Characterisation

(102) For the 1:8.6 (SX)/1:2.5 (FP) blends typical tablet weights were between 0.0633-0.0793 g for uncoated and 1% coated lactose formulations. The final theoretical menthol concentration in the pMDI canisters was from 0.0077-0.0083% w/w for 1% w/w menthol coated lactose formulations. Further details of these formulations are shown in Table 13.

(103) For the 1:17.2(SX)/1:5(FP) blends typical tablet weights were between 0.1126-0.1227 g for uncoated and 1% coated lactose formulations. The final theoretical menthol concentration in the pMDI canisters was 0.0131-0.0137% w/w for 1% w/w menthol coated lactose formulations. Further details of these formulations are shown in Table 14.

(104) 3.3 Preliminary Aerosol Characterisation

(105) Tables 15 and 16 show the dose characteristics for salmeterol and fluticasone respectively for formulations prepared from a blend of API and lactose with the following weight ratios 1: 8.6 SX:lactose and 1:2.5 FP:lactose. Two control formulations were assessed, i.e. tablets prepared with uncoated lactose and also powder blends that were not compressed into tablets.

(106) In general the tablets with lactose coated with disintegrant were more easily dispersed in the propellant than the un-coated control tablets. The control tablets even after hand shaking/mechanical shaking and sonication contained large agglomerates of powder.

(107) Tables 15 and 16 show that the aerosol and dose characteristics i.e. FPF and FPD for both the SX and FP were in good agreement with the reference product (Seretide). The metered doses for these non-optimised novel formulations were also in line with the reference product.

(108) The characteristics determined for the 1:8.6 SX:1:2.5 FP:lactose formulations were also observed for the 1:17.2 SX:1:5 FP:lactose formulations. Tables 17 and 18 summarise the aerosol and dose characteristics, the fine particle fractions and the fine particle doses delivered via the construct formulations compared favourably with the Reference Product.

EXAMPLE 4

(109) 4.1 Test Formulation—Soluble API Beclometasone Dipropionate

(110) Propellant disintegratable compressed dosage forms (tablets) containing a soluble API namely, Beclometasone Dipropionate (BDP), was prepared and used to formulate pressurized metered dose inhalers.

(111) The formulations were designed to deliver approximately 50 μg of BDP per metered dose (200 doses) i.e. to be comparable with the QVAR® (Reference product, Teva UK Limited, UK) a commercially available solution form of beclomethasone dipropionate in HFA 134a. QVAR® was tested using its standard actuator.

(112) Inspection of Table 19 illustrates the uniformity of the BDP:Lac powder blends. The RSD values of the powder blends were below 2% for all formulations. The BDP recoveries from the powder blends of the 1:2 coated and the 1:5 uncoated were approximately 112 and 85% respectively of the target. In the preparation of pMDI from these powder blends the mass of propellant added to the canisters was adjusted so as to provide 50 μg per actuation of BDP.

(113) Typical construct weights for the 1:5 w/w BDP:Lactose blends were in the range 0.066-0.084 g. For the 1:2 w/w BDP:Lactose blends tablet weights ranged from 0.0401-0.0504 g.

(114) 4.2 Preliminary Aerosol Characterisation

(115) BDP has a degree of solubility in HFA 134a, the extent of which makes suspension systems untenable due to the potential for API dissolution and subsequent crystal growth leading to unstable suspension systems. However, the addition of a small quantity of ethanol i.e. approx. 5% w/w is adequate to ensure sufficient solubility of BDP for at least 50 μg/actuation solution systems.

(116) The dose characteristics and aerosol properties using an actuator with a 0.4 mm orifice diameter are shown in Table 20. Inspection of the PET vials for the BDP alone control formulation showed a clear solution indicating that the BDP was dissolved in the 5% w/w ethanol:HFA medium. For all formulations the majority of the BDP in the NGI (i.e. that not impacted in the Induction Port) was deposited on stages with effective cut-off diameters of less than 2.3 μm, with significant deposition below the micro-orifice collector (MOC<0.54 μm). This type of deposition pattern is indicative of an API being dissolved in the propellant system.

(117) The dose characteristics and aerosol data shown in Table 21 were generated using the same pMDI units described above. However for these tests a 0.25 mm orifice diameter actuator was used. Consequently a finer and slower moving aerosol plume was generated i.e. reduced ballistic impaction. The aerodynamic particle size distribution of the novel formulations was shifted towards the right and was more closely aligned with that of the Reference product. Key aerosol parameters demonstrate this, in particular the FPF increased to match or exceed the Reference product.

(118) Overall this provides proof of concept that following blending, non-micronised soluble API and lactose (coated and uncoated), can be compressed into tablet form and dispersed in a propellant system incorporating a co-solvent e.g. HFA 134a/ethanol blend, in which the soluble API subsequently dissolved. The dose properties and aerosol characteristics of the formulations were shown to compare favourably with marketed reference products.

EXAMPLE 5

(119) 5.1 Test Formulation—Combination Soluble and Insoluble API

(120) Soluble APIs may also be formulated in combination systems with insoluble suspended API, this is exemplified by the solution/suspension combination formulation of salbutamol sulphate (SS) and beclometasone dipropionate (BDP) where SS is in suspension and BDP is in solution.

(121) Inspection of Table 22 illustrates the uniformity of the BDP/SS:Lac powder blends. The RSD values of the powder blends were below 2% for all formulations. Typical tablet weights were between 0.1771-0.1999 g and 0.0862-0.1038 g for uncoated and coated tablets respectively.

(122) 5.2 Preliminary Aerosol Characterisation

(123) The dose characteristics and aerosol properties are shown in Tables 23 and 24.

(124) The BDP data (Table 23) i.e. soluble API, show similar aerodynamic particle size distributions as QVAR®, resulting in fine particle fraction (range 70.70 81.12%<5 μm) values similar to the Reference product (72.96%<5 μm). The fine particle doses (range 32.26-35.74 μg) were also similar to that of QVAR® (26.54 μg).

(125) Salbutamol sulphate data i.e. the suspended API, are shown in Table 24. Ventolin Evohaler (GSK) and Airomir (Teva) were assessed as the Reference products. Neither Reference formulation was an exact match for the Test formulation in that Ventolin does not contain any ethanol or other excipients, however the volume of the metered dose i.e. 50 μL matches that of the Test formulations. Whilst Airomir does contain ethanol it also has a surfactant (oleic acid) and utilises a smaller valve metering chamber (25 μL).

(126) Table 24 shows the metered doses (emitted doses) per actuation for these non-optimised formulations.

(127) In general the fine particle fraction data (range 43.02-54.62%<5 μm) matched or exceeded those of the Reference products (range 36.01-48.80%<5 μm). As a consequence of the metered (emitted) dose exceeding the target the fine particle mass was also superior to the Reference products.

(128) When actuated through a 0.25 mm diameter actuator orifice the aerosol so formed had characteristics similar to those observed for the two marketed products tested individually.

(129) Summary

(130) Experiments to investigate the disintegration, in propellant HFA 134a, of tablets formed by the direct compression of lactose showed poor dispersion of the tablets. Consequently the solubility of a range of compounds identified as possible disintegrants i.e. materials to be included in the tablet that would promote dispersion in HFA propellants, were evaluated.

(131) A range of materials i.e. glycerol, PEG 400, Tween 80, PVP and PG, showed limited solubility (approx. range 0.05-0.1% w/w) in HFA propellants. Menthol, in contrast was found to be soluble at concentrations of approx.≤3% w/w in HFA 134a and 227.

(132) Samples of lactose were coated with selected disintegrants at concentrations of either 1 or 5% w/w.

(133) Since menthol showed the greatest solubility in the propellant this was identified as the material most likely to enhance disintegration of the compressed dosage forms.

(134) Consequently menthol coated lactose was blended with a model API (SS) and compressed into tablets, dispensed into aerosol cans and metering valves crimped to seal the cans. Upon addition of propellant HFA 134a to the aerosol container the tablets were observed to disperse primarily by hand shaking, although ball bearings/plastic ‘peas’ or sonication was required to disrupt some small aggregates.

(135) Following dispersion of the tablet the resulting suspension system within the aerosol container was expected to demonstrate similar properties to formulations described in the original PCT filing (3).

(136) The key aerosol characteristics of this non-optimised test formulation compared favourably with the reference product (Ventolin® Evohaler). The concentration of menthol in terms of the propellant was very low i.e. approx. 0.4% % w/w (Table 7) thus it is anticipated that increasing the amount of menthol associated with the lactose may improve disintegration of the tablet. Solubility results show that the menthol concentration could be increased several-fold (see Table 3).

(137) Additionally, it has been shown that both soluble and insoluble APIs can be prepared and delivered in this way.

(138) Further, it has been shown that a combination of APIs can be effectively prepared and delivered and a dose equivalent to or greater than existing systems. This is particularly advantageous as it permits delivery of multiple therapeutics in a single controlled dose.

(139) Additionally, it has been shown that two API's with differing physicochemical properties (i.e. micronised versus non-micronised) and differing therapeutic targets (i.e. anti-inflammatory versus bronchodilator) can be successfully blended together and compressed into a tablet, and importantly, dispersed without the need for mechanical shaking or sonication. Additionally, formulations prepared without disintegrant were also shown to disperse and the suspension/solution systems so formed demonstrated acceptable aerosol properties. This provides the ability to prepare both soluble and insoluble APIs in the preparation of pMDIs which previously proved troublesome.

(140) Consequently, the technique disclosed herein could potentially greatly simplify the filling process by removing the requirement to perform complex pressurized single stage fills i.e. re-cycling homogenised suspension of micronised API at high pressures. Also steps such as determining when the pressure vessel required topping up with propellant (to account for evaporation into the head space) and sampling re-circulating suspension to determine API levels would become obsolete.

REFERENCES

(141) To be completed based on those references retained above. 1. U.S. Pat. No. 5,776,432. 2. WO 98/56349 3. WO 99/51205 4. WO 2008/053250

(142) TABLE-US-00001 TABLE 1 Conc. Wt of Additive Material Wt 134a (% w/w) Soluble Vial Material (g) (g) 134a (Y/N/) 1 Glycerol 0.00090 10.5334 0.009 Y 2 Glycerol 0.0067 10.5727 0.063 N 3 Tween 80 0.00097 10.5842 0.009 Y 4 Tween 80 0.0083 10.5607 0.079 Y 5 PEG 400 0.0099 10.5703 0.094 Y 6 PEG 400 0.0055 10.6284 0.052 Y

(143) TABLE-US-00002 TABLE 2 Conc. Wt of Additive Material Wt HFA (% w/w) in Soluble Vial Material (g) (g) Propellant (Y/N) *1 Menthol 0.0051 11.7946 0.0432 Y *2 Menthol 0.0174 11.9227 0.1457 Y *3 PVP 0.0062 11.9582 0.0518 Y *4 PEG 6000 0.0103 12.0205 0.0856 N *5 Na Bicarbonate 0.0040 11.7518 0.0340 N *6 Citric Acid 0.0091 11.9981 0.0758 N *7 PG 0.0098 11.5224 0.0850 Y .sup.#8 Menthol 0.0070 10.7485 0.0651 Y .sup.#9 PVP 0.0063 10.8160 0.0582 N .sup.#10 PEG 6000 0.1020 10.7120 0.9432 N .sup.#11 Na Bicarbonate 0.0066 10.9173 0.0604 N .sup.#12 Citric Acid 0.0071 10.9377 0.0649 N .sup.#13 PG 0.0093 10.9534 0.0848 Y

(144) TABLE-US-00003 TABLE 3 Conc. Material Wt of Additive Descrip- Material Wt HFA (% w/w) Vial tion (g) (g) 134a Observations *1 Menthol 0.0941 9.8298 0.9482 Soluble *2 Menthol 0.3076 9.9939 2.9860 Insoluble, thin crystals at interface adhering to vial *3 PVP 0.0977 9.8169 0.9854 Insoluble, wetted material creamed at interface *4 PVP 0.2768 9.9776 2.6993 As above *5 PG 0.0974 9.7900 0.9851 Insoluble droplets adhering to sides of vial *6 PG 0.2930 10.0344 2.8371 As above #7 Menthol 0.1014 9.4114 1.0659 Soluble #8 Menthol 0.3233 8.7691 3.5557 Insoluble, long thin needle like crystals #9 Menthol 0.5103 7.7642 6.1671 As above #10 PVP 0.1100 9.5586 1.1377 Insoluble, particles, tending to floculate #11 PVP 0.2971 7.2789 3.9216 As above #12 PG 0.1011 18.1890 0.5528 Insoluble, droplets at interface #13 PG 0.2966 9.7761 2.9446 As above #14 PG 0.4980 9.9361 4.7728 As above

(145) TABLE-US-00004 TABLE 4 Target Actual Conc. Glycerol PEG Tween Menthol Lactose Conc. (% w/w) (g) 400 (g) 80 (g) (g) PVP (g) PG (g) (g) (% w/w) 1% 0.2014 — — — — — 19.8000 1.02 5% 1.0167 — — — — — 19.0453 5.34 1% — 0.2004 — — — — 19.8146 1.01 5% — 1.0030 — — — — 19.0000 5.28 1% — — 0.2070 — — — 19.8300 1.04 5% — — 0.9919 — — — 19.0074 5.22 1% — — — 0.1996 — — 19.8010 1.00 1% — — — — 0.2009 — 19.8022 1.00 1% — — — — 0.2025 19.8068 1.0

(146) TABLE-US-00005 TABLE 5 Blend Details SS (g) Lactose (g) % SS (w/w) 1% Menthol 0.4728 8.9939 4.99 1% PG 0.4729 8.9947 4.99 1% PVP 0.4723 9.0001 4.99 Lactose (Control) 0.4725 9.0008 4.99

(147) TABLE-US-00006 TABLE 6 Formulation Sample Mass Theoretical Actual % Details (g) SS (g) SS (g) Theoretical 1% Menthol 0.1987 0.0099 0.0095 95.81 (Coated 0.1711 0.0085 0.0083 97.04 Lactose) 0.1985 0.0099 0.0100 100.90 Mean 97.92 SD 2.65 RSD 2.71 1% PG 0.1917 0.0096 0.0097 101.51 (Coated 0.2039 0.0102 0.0103 101.16 Lactose) 0.2139 0.0107 0.0112 104.49 Mean 102.39 SD 1.83 RSD 1.79 1% PVP 0.2068 0.0103 0.0100 96.44 (Coated 0.2216 0.0111 0.0110 99.01 Lactose) 0.2476 0.0124 0.0122 98.56 Mean 98.00 SD 1.37 RSD 1.40 Control 0.3041 0.0152 0.0166 109.25 (Uncoated 0.3157 0.0157 0.0165 104.72 Lactose) 0.3065 0.0153 0.0166 108.31 Mean 107.43 SD 2.39 RSD 2.23

(148) TABLE-US-00007 TABLE 7 Conc. Lac Conc. Vial Formulation Wt of Wt Total Wt of Filled (% w/w) Menthol (% Number Description tablet (g) 134a (g) Formulation (g) 134a w/w) 134a *1 1% Menthol - Tab 0.3295 9.1730 9.5029 3.4675 0.0358 *2 1% Menthol - Tab 0.4299 9.1532 9.5833 4.4860 0.0468 *3 1% Menthol - Tab 0.3907 9.2909 9.6821 4.0355 0.0419 .sup.#4 Control 1% Menthol 0.3518 9.3789 9.3785 3.6154 0.0374 .sup.#5 Control 1% Menthol 0.3391 9.5533 9.5530 3.4279 0.0354 .sup.#6 Control 1% Menthol 0.4333 9.5715 9.5711 4.3309 0.0452 .sup.§7 Control Lac 0.3025 9.4364 9.4361 3.1061 — .sup.§8 Control Lac 0.3062 9.3829 9.3826 3.1603 — .sup.§9 Control Lac 0.4125 9.4851 9.4847 4.1677 —

(149) TABLE-US-00008 TABLE 8 *1% .sup.#1% Menthol Menthol .sup.§Lactose Ventolin ® Formulation Tablet Control Control Evohaler Metered (Shot) 82.10 69.38 65.78 0.07 Weight (mg) Metered Dose/Actuation N/D 179.71 132.39 N/D inc. Actuator (μg) Emitted SS Per Actuation 118.78 148.74 108.98 99.67 (ex Actuator) (μg) SS FPF (% < 5 μm) 42.26 43.28 35.66 49.35 SS FPD (μg < 5 μm) 50.20 64.37 38.86 40.82 (ex device)

(150) TABLE-US-00009 TABLE 9 .sup.#1% Ventolin ® *1% Menthol .sup.§Lactose Evohaler Formulation Menthol Control Control Reference Induction Port 22.13 23.08 23.70 45.37 Stage 1 (ECD = 11.72 μm) 25.62 24.07 33.25 1.73 Stage 2 (ECD = 6.4 μm) 5.48 4.47 3.97 1.49 Stage 3 (ECD = 3.99 μm) 8.69 9.89 6.54 4.66 Stage 4 (ECD = 2.3 μm) 15.31 17.96 13.73 17.75 Stage 5 (ECD = 1.36 μm) 13.97 12.63 10.69 18.81 Stage 6 (ECD = 0.83 μm) 5.50 5.45 5.12 7.43 Stage 7 (ECD = 0.54 μm) 2.56 1.92 2.14 2.06 MOC 0.74 0.53 0.87 0.69

(151) TABLE-US-00010 TABLE 10 SX FP Lactose % SX % FP Blend Details (g) (g) (g) (w/w) (w/w) 1:8.6 (SX)/ 0.3498 1.2051 2.9227 7.81 26.91 2.5 (FP):Coated Lactose 1:17.2 (SX)/ 0.2332 0.8030 3.9039 4.72 16.25 5 (FP):Coated Lactose

(152) TABLE-US-00011 TABLE 11 Formulation Sample Theoretical Actual Theoretical Details Mass (g) API (mg) API (mg) (%) 1:8.6 0.0739 5.6546 5.4381 96.17 (SX)/:Un-coated 0.0739 5.6546 5.6259 99.49 Lactose 0.0739 5.6546 5.5707 98.82 Mean 98.06 SD 1.71 RSD 1.74 1:2.5 0.0739 19.4897 19.0798 97.85 (FP):Un-coated 0.0739 19.4987 19.6694 100.88 Lactose 0.0739 19.4987 19.5955 100.50 Mean 99.74 SD 1.65 RSD 1.65 1:8.6 0.0739 5.6546 5.5788 98.66 (SX)/:1% 0.0739 5.6546 5.6090 99.19 coated 0.0739 5.6546 5.5899 98.86 Lactose Mean 98.90 SD 0.27 RSD 0.27 1:2.5 0.0739 19.4897 19.5370 100.20 (FP):1% 0.0739 19.4987 19.4349 99.67 coated 0.0739 19.4987 19.9922 102.53 Lactose Mean 100.80 SD 1.52 RSD 1.51

(153) TABLE-US-00012 TABLE 12 Formulation Sample Theoretical Actual Theoretical Details Mass (g) SS (mg) SS (mg) (%) 1:17.2 0.1227 5.6571 5.5221 97.61 (SX)/:Un-coated 0.1227 5.6571 5.6826 100.45 Lactose 0.1227 5.6571 5.6099 99.17 Mean 99.08 SD 1.42 RSD 1.43 1:5 0.1227 19.5072 19.3246 99.06 (FP):Un-coated 0.1227 19.5072 19.9174 102.10 Lactose 0.1227 19.5072 19.8502 101.76 Mean 100.98 SD 1.66 RSD 1.65 1:17.2 0.1227 5.6571 5.6976 100.72 (SX)/:1% 0.1227 5.6571 5.7033 100.82 coated 0.1227 5.6571 5.6813 100.43 Lactose Mean 100.65 SD 0.20 RSD 0.20 1:5 0.1227 19.5072 20.1627 103.36 (FP):1% 0.1227 19.5072 20.1625 103.36 coated 0.1227 19.5072 20.2293 103.70 Lactose Mean 103.47 SD 0.20 RSD 0.19

(154) TABLE-US-00013 TABLE 13 Total wt of Conc. Filled Conc. Lac Menthol Formulation Wt of Wt 134a Formulation (% (% w/w) Vial Description Tablet (g) (g) (g) w/w)134a 134a 1* 1:8.6(SX)/2.5(FP): 0.0793 9.2047 9.2840 0.85 Un-coated Lactose Tab 2* 1:8.6(SX)/2.5(FP): 0.0633 9.0227 9.0860 0.70 Un-coated Lactose Tab 3* 1:8.6(SX)/2.5(FP): 0.0657 9.0526 9.1183 0.72 Un-coated Lactose Tab 4.sup.# 1:8.6(SX)/2.5(FP): 1% 0.0703 9.2559 9.3262 0.75 0.0077 Menthol Tab (Coated Lactose) 5.sup.# 1:8.6(SX)/2.5(FP): 1% 0.0726 9.0401 9.1127 0.80 0.0081 Menthol Tab (Coated Lactose) 6.sup.# 1:8.6(SX)/2.5(FP): 1% 0.0702 9.0305 9.1007 0.77 0.0079 Menthol Tab (Coated Lactose) 7.sup.¥ 1:8.6(SX)/2.5(FP): 1% 0.0738 9.0342 9.1080 0.81 0.0083 Menthol Cont (Coated Lactose) 8.sup.¥ 1:8.6(SX)/1:2.5(FP): 0.0738 9.0285 9.1023 0.81 0.0083 1% Menthol Cont (Coated Lactose 9.sup.¥ 1:8.6(SX)/1:2.5(FP): 0.0738 9.0536 9.1274 0.81 0.0082 1% Menthol Cont (Coated Lactose

(155) TABLE-US-00014 TABLE 14 Total wt of Conc. Wt of Filled Conc. Lac Menthol Vial Formulation Tablet Wt 134a Formulation (% (% w/w) Number Description (g) (g) (g) w/w)134a 134a 1* 1:17.2(SX)/1:5(FP): 0.1171 9.2829 9.4000 1.25 Un-coated Tab 2.sup.# 1:17.2(SX)/1:5(FP): 0.1195 9.2352 9.3547 1.28 0.0131 1% Menthol Tab (Coated Lactose) 3.sup.¥ 1:17.2(SX)/1:5(FP): 0.1227 9.0568 9.1795 1.34 0.0137 1% Menthol Cont (Coated Lactose) 4.sup.¥ 1:17.2(SX)/1:5(FP): 0.1226 9.0542 9.1768 1.34 0.0137 1% Menthol Cont (Coated Lactose) 5.sup.¥ 1:17.2(SX)/1:5(FP): 0.1126 9.1201 9.2427 1.33 0.0136 1% Menthol Cont (Coated Lactose)

(156) TABLE-US-00015 TABLE 15 1% Menthol Uncoated 1% Menthol Uncompressed Seretide Tablet Tablet Control Evohaler ® Metered (shot) 65.36 ± 2.73 64.34 ± 1.66 65.23 ± 0.49 72.92 ± 0.18 Weight (mg) Metered Dose/Actuation 47.04 ± 5.68 37.47 ± 3.37 38.90 ± 2.93 33.94 ± 4.06 inc. Actuator (μg) Emitted SX/Actuation 42.90 ± 6.36 33.52 ± 2.65 35.97 ± 2.69 28.96 ± 2.87 (ex-Actuator) (μg) SX FPF (% < 5 μm) 46.26 ± 1.83 64.09 ± 3.79 62.02 ± 0.19 53.27 ± 3.78 SX FPD (μg < 5 μm) 19.92 ± 3.63 21.54 ± 2.88 22.31 ± 1.67 15.40 ± 1.37

(157) TABLE-US-00016 TABLE 16 1% Menthol Uncoated 1% Menthol Uncompressed Seretide Tablet Tablet Control Evohaler ® Metered (shot) 65.36 ± 2.73 64.34 ± 1.66 65.23 ± 0.49 72.92 ± 0.18 Weight (mg) Metered Dose/Actuation 160.74 ± 15.91 132.71 ± 11.38 139.02 ± 10.84 131.14 ± 17.69 inc. Actuator (μg) Emitted FP/Actuation 146.61 ± 18.50 118.44 ± 8.90  128.36 ± 9.89  112.34 ± 12.26 (ex-Actuator) (μg) FP FPF (% < 5 μm) 47.77 ± 1.33 63.20 ± 3.69 62.48 ± 0.87 53.18 ± 4.17 FP FPD (μg < 5 μm)  70.20 ± 10.66 75.05 ± 9.69 80.13 ± 5.11 59.54 ± 4.99

(158) TABLE-US-00017 TABLE 17 1% Menthol Uncoated 1% Menthol Uncompressed Seretide Tablet Tablet Control Evohaler ® Metered (shot) 65.64 70.30 64.57 ± 0.63 72.92 ± 0.18 Weight (mg) Metered 40.51 40.49 45.03 ± 0.44 33.94 ± 4.06 Dose/Actuation inc. Actuator (μg) Emitted 34.66 37.60 41.48 ± 0.47 28.96 ± 2.87 SS/Actuation (ex-Actuator) (μg) SX FPF (% < 5 μm) 50.53 56.86 54.68 ± 1.48 53.27 ± 3.78 SX FPD (μg < 5 μm) 17.51 21.38 22.68 ± 0.60 15.40 ± 1.37

(159) TABLE-US-00018 TABLE 18 1% Menthol Uncoated 1% Menthol Uncompressed Seretide Tablet Tablet Control Evohaler ® Metered (shot) 65.64 70.30 64.57 ± 0.63 72.92 ± 0.18 Weight (mg) Metered 141.94 144.13 159.23 ± 0.86  131.14 ± 17.69 Dose/Actuation inc. Actuator (μg) Emitted 121.38 133.84 146.50 ± 1.36  112.34 ± 12.26 SS/Actuation (ex-Actuator) (μg) FP FPF (% < 5 μm) 50.51 54.68 53.22 ± 1.52 53.18 ± 4.17 FP FPD (μg < 5 μm) 61.31 73.18 77.96 ± 1.94 59.54 ± 4.99

(160) TABLE-US-00019 TABLE 19 1:2 - 1:5 - 1:2 - BDP:Lac 1% 1:5 - BDP:Lac 1% Sample BDP:Lac Menthol BDP:Lac Menthol Number Uncoated Coated Uncoated Coated 1 102.38 111.92 85.90 100.23 2 99.57 112.66 86.54 97.69 3 103.41 109.90 83.81 101.23 MEAN 101.79 111.49 85.42 99.72 SD 1.99 1.43 1.43 1.83 RSD 1.95 1.28 1.67 1.83

(161) TABLE-US-00020 TABLE 20 BDP only 1:5 Control 1:5 1% Menthol 1:5 Control 1:5 1% Menthol QVAR ® Control Powder Powder Tablet Tablet Mean Metered (Shot) 63.82 62.12 63.14 62.94 61.50 60.35 Weight (mg) Metered Dose 71.44 61.66 66.28 53.14 56.17 43.99 BDP/Actuation inc. Actuator (μg) Emitted Dose 63.90 55.37 58.63 48.07 49.27 36.35 BDP/Actuation (ex Actuator) (μg) BDP FPF (% < 5 μm) 40.28 41.61 41.55 44.33 42.89 72.96 BDP FPD (μg < 25.74 23.04 24.36 21.31 21.13 26.54 5 μm) (ex device)

(162) TABLE-US-00021 TABLE 21 *1:5 *1:5 1% 1:5 BDP Control Menthol Control QVAR ® only Powder Powder Tablet Mean Metered (Shot) 62.82 61.66 61.60 62.94 60.35 Weight (mg) Metered Dose 66.98 56.42 65.95 58.33 43.99 BDP/Actuation inc. Actuator (μg) Emitted Dose 62.17 52.94 58.83 54.22 36.35 BDP/Actuation (ex Actuator) (μg) BDP FPF (% < 5 μm) 79.49 82.15 67.72 80.86 72.96 BDP FPD (μg < 5 μm) 49.42 43.48 39.84 43.85 26.54 (ex device)

(163) TABLE-US-00022 TABLE 22 1:12/(1:5) - 1:12/(1:5) - BDP/SS:Lactose BDP/SS:Lactose 1% UnCoated Menthol Coated Sample Number SS BDP SS BDP 1 94.93 87.11 96.41 92.23 2 95.46 90.00 99.00 92.69 3 95.78 88.05 97.52 92.61 Average 95.39 88.38 97.64 92.51 SD 0.43 1.48 1.30 0.24 RSD 0.45 1.67 1.33 0.26

(164) TABLE-US-00023 TABLE 23 Uncoated 1% Menthol Uncoated Uncoated 1% Menthol 1% Menthol Canister Number Powder Coated Powder Tablet Tablet Coated Tablet Coated Tablet QVAR ®Mean Metered (Shot) Weight 62.3 62.3 60.9 63.4 60.3 61.6 60.35 (mg) Metered Dose BDP/ 47.11 49.57 46.43 48.71 51.01 47.22 43.99 Actuation inc. Actuator (μg) Emitted Dose BDP/ 44.23 45.62 43.92 45.33 47.55 43.62 36.35 Actuation (ex Actuator) (μg) BDP FPF (% < 5 μm) 75.20 70.70 81.12 78.85 70.47 68.90 72.96 BDP FPD (μg < 5 μm) 33.26 32.26 35.63 35.74 33.51 30.06 26.54 (ex device) % of BDP on Actuator 6.11 7.96 5.41 6.94 6.80 7.61 NR

(165) TABLE-US-00024 TABLE 24 1% Menthol Uncoated 1% Menthol 1% Menthol Uncoated Coated Tablet Uncoated Coated Tablet Coated Ventolin ® Airomir ® Canister Number Powder Powder F12 Tablet F13 F12 TabletF13 SS Mean SS Mean Metered (Shot) Weight (mg) 62.3 62.3 60.9 63.4 60.3 61.6 74.35 31.52 Metered Dose SS/Actuation 142.60 165.49 168.89 157.63 155.91 160.25 131.11 122.30 inc. Actuator (μg) Emitted Dose SS/Actuation 119.62 151.23 157.97 147.14 144.04 148.51 113.53 95.59 (ex Actuator) (μg) SS FPF (% < 5 μm) 49.25 43.02 54.62 52.16 50.26 48.47 36.01 48.80 SS FPD (μg < 5 μm) (ex 58.91 65.06 86.28 76.74 72.39 71.98 40.95 46.54 device) % of SS on Actuator 16.11 8.61 6.47 6.66 7.61 7.33 13.41 21.84